The purpose of this study was to determine the initial space of distribution of [14C]erythritol (mol wt 122) and [14C]mannitol (mol wt 182) in the liver of the dog by the single-injection, multiple-indicator-dilution method. 22Na was used as the extracellular indicator and tritiated water (THO) was used as total liver water indicator. The indicators were simultaneously injected into the portal vein of anesthetized dogs and dilution curves were obtained at the outflow from the hepatic vein. It was found that hepatic venous dilution curves of [14C]erythritol and THO were practically identical in all experiments. In contrast, the dilution curves of [14C]mannitol were generally distinct from those of THO. Analysis of [14C]mannitol-dilution curves according to Goresky suggested that the observed difference between this solute and THO was the result of a limited permeability of the sinusoidal membrane to mannitol. It is concluded that [14C]erythritol has instantaneous and practically unrestricted access to total liver water. This finding supports the validity of using erythritol as a liver cell water marker. A larger solute, [14C]mannitol, has restricted access to total liver cell water because of a permeability barrier in the sinusoidal liver cell membrane, but its diffusion into the hepatocyte is also very rapid.